Our previous studies have shown that lymphocytes from some human subjects will respond in vitro to the synthetic polypeptides: (T,G)-A--L, (Phe,G-A--L) and GAT. Preliminary family study suggests that high response to these antigens is inherited as a dominant trait showing segregation with HLA. Gene complementation in response to (T,G)-A--L and (H,G)-A--L is also indicated from two informative families. The aims of this proposal are to elucidate the genetic factors that influence this responsiveness. The study subjects will be unrelated individuals and families of a genetic isolate - the Old Amish population. This group is uniquely suited for these experiments inasmuch as individuals of known HLA genotypes can be selected for in vitro cellular response to the antigens. HLA restriction and Ir gene influence on T cell and macrophage interaction and on T cells, B cells and M-o interaction in antigen specific antibody production will be studied. HLA homozygotes will be tested for immune suppression. Analysis for complementation will be carried out utilizing the inter- and backcross matings as well as intra-HLA recombinants within the Amish families. Segregation analysis will be performed to determine linkage of specific Ir gene with particular HLA haplotypes in the two and three generation families.